Previous Systemic Therapy Research Articles

Prognostic assessment of patients who receive radiotherapy for bone metastases from breast cancer.

For prognostic assessment in women who receive radiotherapy (RT) for bone metastases (BMs) from breast cancer (BC), prognostic factors specific for BMs from BC were investigated in the present study. The prognostic assessment was performed by retrospectively reviewing 143 women who received first-time RT for BMs from BC between January 2007 and June 2018. The median follow-up time and median overall survival (OS) time from the first-time RT for BMs were 22 and 18 months, respectively. In the multivariate analysis, nuclear grade 3 (NG 3) [hazard ratio, 2.18; 95% confidence interval (CI), 1.34-3.53], brain metastases (hazard ratio, 1.96; 95% CI, 1.01-3.81), liver metastases (hazard ratio, 1.75; 95% CI, 1.17-2.63), performance status (PS) (hazard ratio, 1.63; 95% CI, 1.10-2.41) and previous systemic therapy (hazard ratio, 1.58; 95% CI, 1.03-2.42) were significant factors for OS, whereas age, hormone-receptor/human epidermal growth factor receptor 2 status, number of BMs and synchronous lung metastases were not significant factors. When points according to risk levels [unfavorable points (UFPs)] were assigned to each risk factor (1.5 points for NG 3 and brain metastases; and 1 point for PS ≥2, previous systemic therapy and liver metastases), the median OS times of patients with a total number of UFPs ≤1 (n=45), 1.5-3 (n=55) and ≥3.5 (n=43) were 36, 17 and 6 months, respectively. Overall, in patients who received first-time RT for BMs from BC, NG 3, brain/liver metastases, poor PS and previous systemic therapy were unfavorable prognostic factors. Comprehensive prognostic assessment using these factors seemed to be useful for the prediction of prognoses in patients with BMs from BC.

Real-Life Effectiveness and Tolerance of Upadacitinib for Severe Atopic Dermatitis in Adolescents and Adults.

The efficacy and safety of upadacitinib in atopic dermatitis have been defined in clinical trials, but long-term real-life experience, essential for clinical decision-making, is still limited. We aimed to assess the effectiveness and tolerance of upadacitinib in a real-life cohort of adults and adolescents with severe atopic dermatitis in whom previous systemic therapies largely failed. Retrospective cohort study collecting data from adults and adolescents treated with upadacitinib 15 or 30mg per day between July 2021 to August 2022. The outcomes for effectiveness were evaluated by the percentage of patients who achieved a validated Investigator's Global Assessment for atopic dermatitis(vIGA-AD) of 0 (clear) or 1 (almost clear) and/or an improvement of at least 75% on the Eczema Area and Severity Index (EASI 75) at the end of the follow-up. All treatment-emergent adverse events were collected. A total of 29 patients were included (22 adults and 7 adolescents), with a median follow-up of 54.4weeks. At the end of the follow-up, 23 patients (79.3%) reached a vIGA-AD of 0/1, and 24 patients (82.7%) achieved EASI 75. Among patients treated with upadacitinib after initial failure of first- and/or second-line treatment with biologics or baricitinib, 5/7 patients (71.4%) reached a vIGA-AD score of 0/1. Disease control was slightly better in adults than in adolescents (81.8% vs 71.4% reached the efficacy endpoint, respectively). Response rate in patients with upadacitinib 15mg seemed better than in clinical trials or network meta-analysis. Safety data were reassuring; lipid changes were the most frequent adverse event. This real-life study confirms the effectiveness of upadacitinib, particularly for the treatment of atopic dermatitis recalcitrant to conventional systemic agents, biologics or baricitinib. Induced lipid changes require close follow-up.

Role of previous systemic antibiotic therapy on the probability of recurrence after an initial episode of Clostridioides difficile infection treated with vancomycin.

To investigate the role of previous antibiotic therapy in the risk of recurrence after a Clostridioides difficile infection (CDI) treated with vancomycin. Multicentre observational study. Patients with a CDI episode achieving clinical cure with oral vancomycin and followed up 8 weeks were included. Previous antibiotic exposure up to 90 days was collected. Multivariate analysis of predictors of recurrence adjusted by the propensity score (PS) of being previously treated with each non-CDI antibiotic was performed. Two hundred and forty-one patients were included; 216 (90%) had received systemic antibiotics. Fifty-three patients (22%) had a CDI recurrence. Rates of recurrence were lower in those treated with piperacillin/tazobactam in the last month when compared with those not receiving piperacillin/tazobactam [3 (7%) versus 50 (25%); P = 0.01], whereas higher rates were seen in those treated with cephalosporins in the last month [26/87 (30%) versus 27/154 (17%); P = 0.03]. In multivariate analysis controlled by the inverse probability of treatment weighting by PS, receiving ≥5 days of piperacillin/tazobactam in the last month as the last antibiotic regimen prior to CDI was independently associated with a lower risk of recurrence [adjusted OR (AOR) 0.13; 95% CI: 0.06-0.29; P < 0.0001] whereas exposure for ≥5 days to cephalosporins (versus piperacillin/tazobactam) was associated with an increased risk (AOR 10.9; 95% CI: 4.4-27.1; P < 0.0001). Recent use of piperacillin/tazobactam might be associated with a lower risk of CDI recurrence, while recent use of cephalosporins might promote an increased risk. These findings should be considered when treating hospitalized patients.

Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial.

Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III-IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016-004403-31). From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2-29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted. Pfizer.

Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis?

Atezolizumab plus bevacizumab has recently been approved as a new first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). We performed a real-world study to evaluate the impact of the IMbrave150 trial inclusion criteria on the safety and efficacy of treatment outside of clinical trials. We analyzed patients treated with atezolizumab plus bevacizumab for unresectable HCC from four different countries. No specific inclusion and exclusion criteria were applied, except for the absence of previous systemic therapies for HCC. The entire population was split into two groups according to concordance with the inclusion criteria as reported in the IMbrave150 trial in 'IMbrave150-in' and 'IMbrave150-out' patients, and safety and efficacy in the two groups of patients were evaluated. Overall, 766 patients were included in the analysis: 561/766 (73%) in the 'IMbrave150-in' group and 205/766 (27%) in the 'IMbrave150-out' group. Median overall survival (OS) and median progression-free survival (PFS) were 16.3 versus 14.3 months (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.35-0.65; p<0.0001] and 8.3 versus 6.0 months (HR 0.79, 95% CI 0.63-0.99; p=0.0431) in 'IMbrave150-in' and 'IMbrave150-out' patients, respectively. Multivariate analysis confirmed that patients included in the 'IMbrave150-in' group had significantly longer OS compared with patients included in the 'IMbrave150-out' group (HR 0.76, 95% CI 0.47-0.97; p=0.0195). In 'IMbrave150-in' patients, the albumin-bilirubin (ALBI) grade was not associated with OS, whereas in 'IMbrave150-out' patients, those with ALBI grade 1 reported a significant benefit in terms of OS compared with those with ALBI grade 2 (16.7 vs. 5.9 months; HR 4.40, 95% CI 2.40-8.08; p>0.0001). No statistically significant differences were reported in the 'IMbrave150-in' and 'IMbrave150-out' groups in terms of safety profile. Adherence to the IMbrave150 trial inclusion criteria favorably impacts the prognosis of patients receiving atezolizumab plus bevacizumab. Among patients who did not meet the IMbrave150 inclusion criteria, those with ALBI grade 1 could benefit from the treatment.

Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial.

Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. UK National Institute for Health and Care Research.

Magnetic Resonance-Guided Stereotactic Body Radiation Therapy/Hypofractionated Radiation therapy for Metastatic and Primary Central and Ultracentral Lung Lesions

IntroductionThe recent results from the Nordic-HILUS study indicate stereotactic body radiation therapy (SBRT) is associated with high-grade toxicity for ultracentral (UC) tumors. We hypothesized that magnetic resonance-guided SBRT (MRgSBRT) or hypofractionated radiation therapy (MRgHRT) enables the safe delivery of high-dose radiation to central and UC lung lesions. MethodsPatients with UC or central lesions were treated with MRgSBRT/MRgHRT with real-time gating or adaptation. Central lesions were defined as per the Radiation Therapy Oncology Group and UC as per the HILUS study definitions: (1) group A or tumors less than 1 cm from the trachea and/or mainstem bronchi; or (2) group B or tumors less than 1 cm from the lobar bronchi. The Kaplan-Meier estimate and log-rank test were used to estimate survival. Associations between toxicities and other patient factors were tested using the Mann-Whitney U test and Fisher’s exact test. ResultsA total of 47 patients were included with a median follow-up of 22.9 months (95% confidence interval: 16.4–29.4). Most (53%) had metastatic disease. All patients had central lesions and 55.3% (n = 26) had UC group A. The median distance from the proximal bronchial tree was 6.0 mm (range: 0.0–19.0 mm). The median biologically equivalent dose (α/β = 10) was 105 Gy (range: 75–151.2). The most common radiation schedule was 60 Gy in eight fractions (40.4%). Most (55%) had previous systemic therapy, 32% had immunotherapy and 23.4% had previous thoracic radiation therapy. There were 16 patients who underwent daily adaptation. The 1-year overall survival was 82% (median = not reached), local control 87% (median = not reached), and progression-free survival 54% (median = 15.1 mo, 95% confidence interval: 5.1–25.1). Acute toxicity included grade 1 (26%) and grade 2 (21%) with only two patients experiencing grade 3 (4.3%) in the long term. No grade 4 or 5 toxicities were seen. ConclusionsPrevious studies noted high rates of toxicity after SBRT to central and UC lung lesions, with reports of grade 5 toxicities. In our cohort, the use of MRgSBRT/MRgHRT with high biologically effective doses was well tolerated, with two grade 3 toxicities and no grade 4/5.

Efficacy, Safety, and Health-Related Quality of Life With Camrelizumab Plus Pemetrexed and Carboplatin as First-Line Treatment for Advanced Nonsquamous NSCLC With Brain Metastases (CAP-BRAIN): A Multicenter, Open-Label, Single-Arm, Phase 2 Study

IntroductionSystemic treatment options for NSCLC with brain metastases (BMs) are scarce. We evaluated the activity and safety of camrelizumab plus chemotherapy as first-line therapy in patients with advanced nonsquamous NSCLC with BMs. MethodsThis was a multicenter, single-arm, phase 2 trial (NCT04211090) conducted at seven hospitals in China. Eligible patients had treatment-naive metastatic nonsquamous NSCLC and BMs that were asymptomatic or symptoms controlled with dehydration therapy and no previous systemic treatment or local therapy for the target brain lesion. Patients received camrelizumab (200 mg) plus pemetrexed (500 mg/m2) and carboplatin (area under the curve 5) intravenously on day 1 of each 21-day cycle for four cycles, followed by maintenance with camrelizumab (200 mg) and pemetrexed (500 mg/m2) every 21 days until disease progression, unacceptable toxicity, or death. The primary end point was confirmed intracranial objective response rate according to modified Response Evaluation Criteria in Solid Tumors version 1.1, which was primarily analyzed in the efficacy analysis set (EAS). ResultsA total of 45 patients were enrolled and treated (full analysis set), with 40 patients having at least one post-baseline tumor assessment (EAS). As of August 30, 2022, median follow-up duration was 12.5 months (95% confidence interval [CI]: 9.2–17.3). The confirmed intracranial objective response rate was 52.5% (95% CI: 36.1–68.5) in EAS and 46.7% (95% CI: 31.7–62.1) in full analysis set. The extracranial objective response rate was 47.5% (95% CI: 31.5–63.9) and 42.2% (95% CI: 27.7–57.8), respectively. Median intracranial progression-free survival was 7.6 months (95% CI: 4.6–not reached [NR]), median overall progression-free survival was 7.4 months (95% CI: 4.4–NR), and median overall survival was 21.0 months (95% CI: 15.9–NR). The most common treatment-related adverse events of grade 3 or higher were neutrophil count decrease (six [13.3%]) and anemia (four [8.9%]). One treatment-related death occurred owing to immune-related pneumonia. Linear mixed-effects model displayed that a positive trend for improvement in cognitive function and quality of life was observed based on Montreal Cognitive Assessment and Functional Assessment of Cancer Therapy—Lung scores (p = 0.025, p < 0.001). ConclusionsCamrelizumab plus pemetrexed and carboplatin was found to have an activity with manageable toxicity and to improve cognitive function and quality of life for patients with nonsquamous NSCLC with BMs in the first-line setting.

Camrelizumab plus low-dose apatinib and SOX in the first-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: A single-arm, dose escalation and expansion study (SPACE study).

365 Background: The dose escalation phase was presented early, and confirmed that the recommended phase II dose (RP2D) was camrelizumab (200 mg, d1) plus apatinib (250 mg, qd), S-1(40 mg, bid, d1-14) and oxaliplatin (130 mg/m2, d1) every 3 weeks followed by camrelizumab (200 mg, d1) plus apatinib (250 mg, qd) every 3 weeks. Methods: Patients (pts) aged 18-75 years, with unresectable or potentially resectable G/GEJ adenocarcinoma, HER2-negative or unknown HER2 status and no previous systemic therapy, were enrolled to receive combination therapy. Primary endpoint was Objective response rate (ORR) by RECIST 1.1, secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), surgical resection rate and safety. Results: From Jun, 2020 to July 2022, 35 pts were enrolled (9 pts in dose escalation phase, 26 pts in dose expansion phase), with a median follow-up of 8.0 months (95% CL, 6.7-12.2). Median age (range) was 59(19-68), 94.3% (33/35) were male, 20% (7/35) were diagnosed with GEJ adenocarcinoma, 60% (21/35) had liver metastases. At data cutoff, 33 pts were included in the efficacy analysis. The ORR was 90.9%, with 30 (90.9%) PR. SD were 1 (3.0%) with a DCR of 93.9%. In addition, 9 pts showed an unconfirmed PR with a confirmed ORR of 80.8%. Median PFS was 10.2 months (95% CI, 5.5-22.3), with the median OS not reached yet. Conversion to resectable G/GEJ adenocarcinoma was identified in 9 (25.7%) pts. Of them, 2 pts were observed complete pathology response. 94.3% pts experienced treatment related adverse event (TRAE), with 45.7% being grade ≥3. The most frequent grade ≥3 TRAE were GGT increased (31.4%, 11/35), rash (11.4%, 4/35), alkaline phosphatase increased (11.4%, 4/35)、neutrophil count decreased (8.6%, 3/35). No new safety signal was identified. Conclusions: Camrelizumab plus apatinib and SOX followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as first line therapy for patients with G/GEJ adenocarcinoma. Clinical trial information: ChiCTR2000034109 .

Effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters and methotrexate for patients with moderate-to-severe psoriasis: a cohort study from BADBIR.

Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Objectives To determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis. Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were ≥ 16 years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with ≥ 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) ≤ 2 reported ≥ 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI ≤ 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data. In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI ≤ 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42-0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46-0.74), comorbidities (aOR 0.70, 95% CI 0.51-0.97) and alcohol consumption (≤ 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50-0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12 months [survival estimate 46.1 (95% CI 44.0-48.3), 31.9 (95% CI 29.4-34.7), 30.0 (95% CI 27.5-32.4) and 35.0 (95% CI 29.9-40.9), respectively]. The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.

Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.

A propensity score–weighted study comparing a two- versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer

BackgroundKRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy of sotorasib, a KRAS G12C inhibitor, in previously treated patients with KRAS p.G12C–mutated pancreatic cancer are unknown.MethodsWe conducted a single-group, phase 1–2 trial to assess the safety and efficacy of sotorasib treatment in patients with KRAS p.G12C–mutated pancreatic cancer who had received at least one previous systemic therapy. The primary objective of phase 1 was to assess safety and to identify the recommended dose for phase 2. In phase 2, patients received sotorasib at a dose of 960 mg orally once daily. The primary end point for phase 2 was a centrally confirmed objective response (defined as a complete or partial response). Efficacy end points were assessed in the pooled population from both phases and included objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Safety was also assessed.ResultsThe pooled population from phases 1 and 2 consisted of 38 patients, all of whom had metastatic disease at enrollment and had previously received chemotherapy. At baseline, patients had received a median of 2 lines (range, 1 to 8) of therapy previously. All 38 patients received sotorasib in the trial. A total of 8 patients had a centrally confirmed objective response (21%; 95% confidence interval [CI], 10 to 37). The median progression-free survival was 4.0 months (95% CI, 2.8 to 5.6), and the median overall survival was 6.9 months (95% CI, 5.0 to 9.1). Treatment-related adverse events of any grade were reported in 16 patients (42%); 6 patients (16%) had grade 3 adverse events. No treatment-related adverse events were fatal or led to treatment discontinuation.ConclusionsSotorasib showed anticancer activity and had an acceptable safety profile in patients with KRAS p.G12C–mutated advanced pancreatic cancer who had received previous treatment. (Funded by Amgen and others; CodeBreaK 100 ClinicalTrials.gov number, NCT03600883.)

A Multicenter, Retrospective Study Evaluating Clinical Outcomes of Ruxolitinib Therapy In Heavily Pretreated Chronic GVHD Patients With Steroid Failure

Although ruxolitinib is emerging as the treatment of choice for steroid-refractory or -dependent chronic graft versus host disease (cGVHD) based on randomized control trial data, there is relatively little real-world data published on ruxolitinib for this indication. We wanted to evaluate the real-world efficacy and safety of ruxolitinib in cGVHD patients who have failed any previous systemic therapy for cGVHD. We retrospectively evaluated the efficacy of ruxolitinib in 115 heavily pretreated patients with steroid-refractory or -dependent chronic GVHD across 5 transplantation centers. The majority of the study population had severe cGVHD (60%) and received ruxolitinib at the fourth treatment line or beyond (82%, n = 96). The median duration of follow-up in this study population was 13 months. The overall response rate (ORR) was 48.6%, 54.9%, and 48.5% at 3, 6, and 12 months, respectively. Clinical benefit (an outcome metric combining ORR with steroid reduction) was observed in 58.7%, 64.8%, and 60.6% of patients at 3, 6, and 12 months, respectively. Approximately one third of patients (37.9%) were able to discontinue prednisone at 12 months, and 63.8% were able to taper prednisone to a daily dose <0.1 mg/kg at 12 months. Failure-free survival at 12 months was 64.6% (54.1%-73.2%). Multivariate analysis identified that patients with severe cGVHD were at a higher risk of failure because of a therapy switch, whereas a pretransplantation hematopoietic stem cell transplantation–comorbidity index score ≥ 3 was associated with a high risk of failure because of increasing risk of non-relapse mortality. Overall, this study demonstrates the therapeutic efficacy of ruxolitinib for cGVHD in a heavily pretreated real-world population.

Mediastinal and Hilar Lymphadenopathy Treated by SABR

<h3>Purpose/Objective(s)</h3> Mediastinal and hilar lymphadenopathy (MHL) is a frequent pattern of cancer spread, most frequent in lung cancer, but also in others primary disease. Traditionally, the local treatments included surgical resection or conventional RT, with or without systemic treatments. Recently, there is a considerable interest in the application of stereotactic ablative radiotherapy (SABR) for MHL. Safety and efficacy of SABR for mediastinal and hilar lymphadenopathy (MHL) have not yet been established. SABR treatment on ultra-central localizations has been found to be associated with higher rates of severe toxicity. Aim of this study is to evaluate the safety, clinical outcomes of survival and predictive factors of response of SABR on MHL. <h3>Materials/Methods</h3> One hundred and thirteen MHL were treated in 97 patients with SABR, from 2007 to 2021. Patients were more commonly affected by lung tumor (47%). The median age of patients was 67 (range 43-90). The schedule most represented was 30 Gy in 5 fractions (range 23-60 Gy in 1-8 fractions). The medium BED (10) was 81 Gy (range 37.5-120Gy). Twenty-six (23%) cases received a single fraction, 87 (77%) cases received multiple fractions. The patients were classified as oligorecurrent (52%), oligoprogressive (35%), oligometastatic (4%) and oligopersistent (9%). <h3>Results</h3> The median follow-up was 20 months (range 0-130 months). Acute toxicities were: five cases (4%) Grade 1 (in form of pain, fatigue, nausea, vomiting and cough), one case (0.9%) with anemia G2, one case (0.9%) died 3 days after treatment on mediastinal lymph node by esophageal bleeding, G5. One case (0.9%) presented late toxicity with dyspnea Grade 2. The rates of Local Control at 1 and 3 years were 90% and 84%, respectively. The rates of Loco Regional Nodal Control at 1 and 3 years were 84% and 75% respectively. The rates of Distant Nodal Control at 1 and 3 years were 93% and 84%, respectively. The rates of Distant Metastasis Free Survival at 1 and 3 years were 57% and 47%, respectively. The rates of Progression Free Survival at 1 and 3 years were 36% and 20%, respectively. The rates of Overall Survival at 1 and 3 years were 69% and 41%, respectively. Univariate analysis showed that the state of disease was statistically significant correlated with OS with better results for oligometastatic patients (p= 0,044). The number of metastases was statistically significant correlated with OS (p= 0,0046) and with DMFS (p= 0,0121). The DMFS was also correlated with number of previous systemic therapy. Patients receiving more than one line (range: 2-4 lines) of systemic therapy prior to SABR presented the worst results (p=0,0065). <h3>Conclusion</h3> In conclusion, our study showed that SABR on MHL is able to achieve excellent results in terms of local control with acceptable toxicity. More prospective studies are needed to confirm these results.

Pembrolizumab-combination therapy for previously untreated metastatic nonsquamous NSCLC: Real-world outcomes at US oncology practices.

The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumab-combination) for patients with metastatic nonsquamous NSCLC in the real-world setting of oncology clinics in the United States (US). Using deidentified, longitudinal patient records from a nationwide, electronic health record-derived US database, we identified patients with metastatic nonsquamous NSCLC, without EGFR/ALK/ROS1 genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumab-combination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier. Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression ≥50%, 1-49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month on-treatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression ≥50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median real-world progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the real-world response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8). These findings demonstrate the benefits of first-line pembrolizumab-combination therapy for patients with EGFR/ALK-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics.

Efficacy and safety of sintilimab plus doxorubicin in advanced soft tissue sarcoma: A single-arm, phase II trial.

Background: Chemoimmunotherapy is safe and efficacious in treating many types of malignant tumors. However, clinical data demonstrating the effect of this combination treatment in patients with metastatic soft tissue sarcoma (STS) are currently limited. This study evaluated the safety and efficacy of a programmed cell death protein 1 (PD-1) inhibitor plus doxorubicin in patients with advanced STS who failed previous systemic therapy. Methods: This was a single-center, single-arm, open-label phase II trial. Patients with unresectable or metastatic STS who had previously failed systemic therapy were enrolled. Patients received up to six cycles of doxorubicin and sintilimab (a PD-1 inhibitor), while sintilimab treatment continued for up to 2years. Primary outcomes were objective response rate (ORR) and safety. Univariate Cox proportional hazards model was used to analyze the relationship between clinicopathological parameters and progression-free survival (PFS). Results: A total of 38 patients (20 men and 18 women) were enrolled in this study. The overall ORR was 39.5%, disease control rate was 71.1%, and the median PFS was 4.5 months [95% confidence interval (CI), 3.0-8.5months]. The adverse events (AEs) associated with the combined treatment were mild, manageable, and well-tolerated. The most common grade 3 or higher AEs were hematologic, including leukopenia (21.1%), anemia (18.4%), and thrombocytopenia (18.4%). Patients with undifferentiated pleomorphic sarcoma (UPS) or dedifferentiated liposarcoma had a significantly longer PFS than those with other pathological subtypes [hazard ratio (HR) = 0.42, 95% CI 0.21-0.83; p = 0.013]. There was no significant difference in the median PFS between patients who had previously received anthracycline-based chemotherapy and those who had not (HR = 0.74, 95% CI 0.34-1.58, p = 0.43). Conclusion: Sintilimab plus doxorubicin is a safe and promising treatment for patients with advanced STS who have failed previous systemic therapy (including anthracycline-based chemotherapy). The efficacy of this combination therapy in UPS and dedifferentiated liposarcoma is superior to that in other sarcomas. Clinical Trial Registration: https://www.chictr.org.cn, registration number: ChiCTR1900027009.

Pucotenlimab: First Approval.

Pucotenlimab (Puyouheng™) is a humanised immunoglobulin (Ig) G4 monoclonal antibody (mAb) being developed by Lepu Biopharma for the treatment of solid tumours, including gastrointestinal cancer, metastatic melanoma, liver cancer, bladder cancer, non-small cell lung cancer and breast cancer. Pucotenlimab binds to PD-1 and blocks its interaction with its ligands, PD-L1 and PD-L2, thereby restoring the ability of immune cells to target cancer cells. In July 2022, pucotenlimab received conditional first approval in China for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumours, including patients with advanced colorectal cancer who have experienced disease progression after previous therapy with fluorouracil, oxaliplatin and irinotecan, as well as patients with other advanced solid tumours who have experienced disease progression after previous first-line therapy and have no satisfactory treatment alternatives. In September 2022, pucotenlimab was approved in China for the treatment of unresectable or metastatic melanomas after the failure of previous systemic therapy. This article summarizes the milestones in the development of pucotenlimab leading to the first approval for the treatment of MSI-H/dMMR advanced solid tumours.

Radiotherapy improves the outcomes of immunotherapy with Sintilimab in non-small-cell lung cancer: A real-world analysis.

IntroductionRadiotherapy may augment systemic antitumor responses to immunotherapy. We did a retrospective study to infer whether radiotherapy improves outcomes to immunotherapy in patients with stage III and IV non-small-cell lung cancer (NSCLC).MethodsThis retrospective study conducted at Enze Medical Center enrolled 259 patients with histopathology confirmed NSCLC from December 2018 to December 31, 2021. All were treated with Sintilimab, some patients received radiotherapy at an appropriate time point. Radiation type includes conventional radiotherapy and stereotactic body radiotherapy. The progression-free survival (PFS), and overall survival (OS) were the primary endpoint.ResultsA retrospective analysis was performed on 259 patients, of whom 140 had been treated with immunotherapy lonely and 119 had been remedied with immunotherapy plus radiotherapy. Baseline variables were well balanced between the two groups, including gender, age, smoking status, TNM staging, number of metastases, ECOG score, pathological type and lines of previous systemic therapy. The median PFS in the immunotherapy alone group was 5.00 months (95%CI 4.38-5.62) versus immunotherapy plus radiotherapy was 9.00 months (5.95-12.05; p<0.001). The median OS in the immunotherapy alone group was 16.00 months (12.59-19.42) versus immunotherapy plus radiotherapy was 30.00 months (20.75-39.25; p=0.027). PFS was finer in the radiotherapy plus immunotherapy group than the immunotherapy group alone in both stage III(P=0.0069) and Stage IV(P=0.006) patients. In the univariate analysis, radiotherapy, male, ECOG=0 and <2 lines of previous systemic therapy were connected with an observably better PFS (P<0.001; P=0.03; P=0.002;P=0.021). In a multivariate analysis, radiotherapy, ECOG=0 and <2 lines of previous systemic therapy were independent prognostic factors with a markedly better PFS (P<0.001; P=0.006;P=0.009). An univariate analysis, radiotherapy, male, stage III, non-metastasis, ECOG=0 and squamous carcinoma were associated with a significantly better OS (P=0.032, P=0.036,P=0.002,P<0.001,P=0.002,P=0.025). A multivariate analysis, non-metastasis was a standalone prognostic indicator with a significantly better OS (P=0.006). However, radiotherapy was a tendency indicator with a better OS (HR0.70 95% CI 0.47-1.06). There were also no obvious increases in adverse events in the combination group.ConclusionsRadiotherapy with addition of immunotherapy was observably linked to a better outcome in patients with III and IV staging NSCLC.

441TiP A multicenter, randomized, open-label, phase III study of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX as first-line therapy in patients with RAS/BRAF wild-type metastatic colorectal cancer

Anlotinib is an oral small molecule tyrosine kinases inhibitor mainly targeting VEGFR 1/2/3, FGFR 1-4, and PDGFR α/β. It has shown potential antitumor activity and manageable safety in patients with RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC) in a phase II study (NCT04080843) when combined with CAPEOX. This phase III study is designed to compare the efficacy and safety of anlotinib plus CAPEOX with standard first-line treatment in patients with RAS/BRAF WT mCRC. This is a multicenter, randomized, open-label, parallel-controlled, non-inferiority, phase III study. Enrolled patients should have an ECOG PS of 0/1 with confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastasis assessed by MDT. Patients classified as MSI-H or dMMR or resectable or potentially resectable metastases or with previous systemic therapy for mCRC will be excluded. A total of 698 patients stratified by primary tumor location and prior adjuvant therapy will be randomized in a 1:1 ratio to anlotinib group or bevacizumab group. Patients in both groups will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), then maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) assessed by an independent review committee. Secondary endpoints are investigator-assessed PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), resection rate of liver metastases, quality of life, and safety. The planned sample size provides 81.2% power to detect a non-inferiority margin of 1.09 in terms of HR for the primary endpoint after 524 events with a one-sided significance level of 0.025. This trial was initiated in May 2021, and enrollment is ongoing. NCT04854668. Chia Tai Tianqing Pharmaceutical Group Co., Ltd.